This invention relates to benzothiophenes, particularly 3-hydroxybenzothiophenes having the 2-sulfide side chains, for example, ##STR1##
These novel benzothiophenes are found to be effective and specific 5-lipoxygenase inhibitors and are therefore useful in the treatment of leukotriene mediated diseases. Furthermore, they are found to be useful as cytoprotective agents.
Among various potent biological mediators derived from the oxygenation of arachidonic acid, prostaglandins and leukotrienes have been linked to various diseases. Notably, the biosynthesis of leukotrienes has been connected to immediate hypersensitivity reactions and pro-inflammatory effects.
It has been established that arachidonic acid undergoes oxygenation via two major enzymatic pathways:
(1) The pathway catalyzed by the enzyme cyclooxygenase; and
(2) The pathway catalyzed by the enzyme 5-lipoxygenase.
Interruption of these pathways by enzyme inhibition has been explored for effective therapy. For example, non-steroidal anti-inflammatory drugs (NSAID) such as indomethacin and diflunisal are known cyclooxygenase inhibitors which inhibit the process wherein arachidonic acid is oxidized via cyclooxygenase to prostaglandins and thromboxanes.
Recently, it has been observed that certain leukotrienes are responsible for diseases related to immediate hypersensitivity reactions such as human asthma, allergic disorders, and skin diseases. In addition, certain leukotrienes and derivatives thereof are believed to play an important role in causing inflammation (B. Samuelsson, Science, 220, 568 (1983); D. Bailey et al, Ann. Rpts. Med. Chem., 17, 203 (1982)).
With respect to the cytoprotective activity of the compounds of the present invention, it has been known that (1) gastric cytoprotection does not involve inhibition of gastric acid secretion. For example, protaglandin F2B does not inhibit gastric acid secretion, but it does induce gastric cytoprotection (S. Szabo et al., Experimentia, 38, 254, 1982); (2) lower effective dosages of cytoprotective agents are required than that of gastric acid inhibitors; (3) it has been observed that specific 5-lipoxygenase inhibitors may also be effective cytoprotective agents; and (4) the cytoprotective activity of a compound may be observed in both animals and man by noting the increased resistance of gastrointestinal mucosa to strong irritants. For example, animal studies have shown that cytoprotective compounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline, etc.